Research on environmental and genetic pathways to complex traits such as educational attainment (EA) is confounded by uncertainty over whether correlations reflect effects of transmitted parental genes, causal family environments, or some, possibly interactive, mixture of both. Thus, an aggregate of thousands of alleles associated with EA (a polygenic risk score; PRS) may tap parental behaviors and home environments promoting EA in the offspring. New methods for unpicking and determining these causal pathways are required. Here, we utilize the fact that parents pass, at random, 50% of their genome to a given offspring to create independent scores for the transmitted alleles (conventional EA PRS) and a parental score based on alleles not transmitted to the offspring (EA VP_PRS). The formal effect of non-transmitted alleles on offspring attainment was tested in 2,333 genotyped twins for whom high-quality measures of EA, assessed at age 17 years, were available, and whose parents were also genotyped. Four key findings were observed. First, the EA PRS and EA VP_PRS were empirically independent, validating the virtual-parent design. Second, in this family-based design, children's own EA PRS significantly predicted their EA (β = 0.15), ruling out stratification confounds as a cause of the association of attainment with the EA PRS. Third, parental EA PRS predicted the SES environment parents provided to offspring (β = 0.20), and parental SES and offspring EA were significantly associated (β = 0.33). This would suggest that the EA PRS is at least as strongly linked to social competence as it is to EA, leading to higher attained SES in parents and, therefore, a higher experienced SES for children. In a full structural equation model taking account of family genetic relatedness across multiple siblings the non-transmitted allele effects were estimated at similar values; but, in this more complex model, confidence intervals included zero. A test using the forthcoming EA3 PRS may clarify this outcome. The virtual-parent method may be applied to clarify causality in other phenotypes where observational evidence suggests parenting may moderate expression of other outcomes, for instance in psychiatry.

Intelligence and educational attainment are strongly genetically correlated. This relationship can be exploited by Multi-Trait Analysis of GWAS (MTAG) to add power to Genome-wide Association Studies (GWAS) of intelligence. MTAG allows the user to meta-analyze GWASs of different phenotypes, based on their genetic correlations, to identify association's specific to the trait of choice. An MTAG analysis using GWAS data sets on intelligence and education was conducted by Lam et al. (2017). Lam et al. (2017) reported 70 loci that they described as ‘trait specific’ to intelligence. This article examines whether the analysis conducted by Lam et al. (2017) has resulted in genetic information about a phenotype that is more similar to education than intelligence.

Blood eosinophil count is associated with a variety of common complex outcomes in epidemiological observation. The aim of this study was to explore the causal association between determined blood eosinophil count and 20 common complex outcomes (10 metabolic, 6 cardiac, and 4 pulmonary). Through Mendelian randomization, we investigated genetic evidence for the genetically determined eosinophil in association with each outcomes using individual-level LifeLines cohort data (n = 13,301), where a weighted eosinophil genetic risk score comprising five eosinophil associated variants was created. We further examined the associations of the genetically determined eosinophil with those outcomes using summary statistics obtained from genome-wide association study consortia (6 consortia and 14 outcomes). Blood eosinophil count, by a 1-SD genetically increased, was not statistically associated with common complex outcomes in the LifeLines. Using the summary statistics, we showed that a higher genetically determined eosinophil count had a significant association with lower odds of obesity (odds ratio (OR) 0.81, 95% confidence interval (CI) [0.74, 0.89]) but not with the other traits and diseases. To conclude, an elevated eosinophil count is unlikely to be causally associated to higher risk of metabolic, cardiac, and pulmonary outcomes. Further studies with a stronger genetic risk score for eosinophil count may support these results.

The aim of this exploratory study was to investigate how sedentary behavior (SB) and physical activity (PA) influence DNA methylation at a global, gene-specific, and health-related pathway level. SB, light PA (LPA), and moderate-to-vigorous PA (MVPA) were assessed objectively for 41 Flemish men using the SenseWear Pro 3 Armband. CpG site-specific methylation in leukocytes was determined using the Illumina HumanMethylation 450 BeadChip. Correlations were calculated between time spent on the three PA intensity levels and global DNA methylation, using a z-score-based method to determine global DNA methylation levels. To determine whether CpG site-specific methylation can be predicted by these three PA intensity levels, linear regression analyses were performed. Based on the significantly associated CpG sites at α = 0.005, lists were created including all genes with a promoter region overlapping these CpG sites. A biological pathway analysis determined to what extent these genes are overrepresented within several pathways. No significant associations were observed between global DNA methylation and SB (r = 0.084), LPA (r = -0.168), or MVPA (r = -0.125), although the direction of the correlation coefficients is opposite to what is generally reported in literature. SB has a different impact on global and gene-specific methylation than PA, but also LPA and MVPA affect separate genes and pathways. Furthermore, the function of a pathway seems to determine its association with SB, LPA, or MVPA. Multiple PA intensity levels, including SB, should be taken into account in future studies investigating the effect of physical (in)activity on human health through epigenetic mechanisms.

Migraine and tension-type headache (TTH) are often viewed as distinct entities and defined as such in the International Classification of Headache Disorders, 2nd edition (ICHD-II) criteria, although there is also empirical evidence to suggest they may be etiologically similar. This study aims to investigate whether migraine and TTH are etiologically related conditions. First, we explored whether migraine and TTH were associated with the same environmental and lifestyle risk factors at the population level. Second, we examined comorbidity of migraine and TTH in a twin design. By comparing the associations in monozygotic (MZ) and dizygotic (DZ) twin pairs, we investigated whether the comorbidity can be explained by genetic factors that influence both conditions. Results indicated that migraine and TTH were largely associated with the same environmental and lifestyle factors, including younger age, female sex, higher body mass index, more depression, stress at home, and less participation in regular exercise, with consistently stronger effects for migraine than for TTH. Migraine in one twin was significantly associated with TTH in the other twin. A stronger cross-trait, cross-twin association in MZ than DZ twins suggested that this comorbidity may also be partly due to shared genetic factors, although the difference in associations was not significant. In conclusion, our findings are consistent with the hypothesis that migraine and TTH have partly shared etiologies. For both treatment and research, it may be advisable not to make a rigid distinction, but to treat migraine and TTH as related conditions.

Social changes, such as the expansion of legal forms of gambling, can influence not only the prevalence of gambling, but can also shape the relative importance of genetic and environmental contributions to individual differences in the propensity to gamble. In the present study, I examined differences in the prevalence and in the relative contribution of genetic and environmental factors to gambling involvement in the United States in 1962 versus 2002. The data came from two sources: (1) a survey of 839 17-year-old same-sex twin pairs from the National Merit Scholarship Qualifying Test twin study, and (2) an interview of 477 18- to 26-year-old same-sex twin pairs from Wave III of the National Longitudinal Study of Adolescent to Adult Health. Similar measures of gambling participation were included in the two studies. Evidence for a genotype-by-time interaction was evaluated by testing whether the contribution of genetic influences was greater in the more recently born cohort of twins. Despite the major changes in the gambling landscape over the intervening 40 years, there was no evidence for such an interaction. The contribution of genetic factors and environmental factors did not significantly differ and there was no evidence for genetic influences at either time point. Instead, the variation in the propensity to gamble was explained nearly equally by common and unique environmental factors. Explanations for this surprising finding are discussed.

The prevalence of overweight and obesity is growing rapidly in many countries. Socioeconomic inequalities might be important for this increase. The aim of this study was to determine associations of body mass index (BMI), overweight and obesity with educational level and marital status in Chinese twins. Participants were adult twins recruited through the Chinese National Twin Registry (CNTR), aged 18 to 79 years, and the sample comprised 10,448 same-sex twin pairs. Current height, weight, educational attainment, and marital status were self-reported. Regression analyses and structural equation models were conducted to evaluate BMI, overweight, and obesity associated with educational level and marital status in both sexes. At an individual level, both educational level and marital status were associated with higher BMI and higher risk of being overweight and obesity in men, while in women the effects of educational level on BMI were in the opposite direction. In within-Monozygotic (MZ) twin-pair analyses, the effects of educational level on BMI disappeared in females. Bivariate structural equation models showed that genetic factors and shared environmental confounded the relationship between education and BMI in females, whereas marital status was associated with BMI on account of significant positive unique environmental correlation apart in both sexes. The present data suggested that marital status and BMI were associated, independent of familiar factors, for both sexes of this study population, while common genetic and shared environmental factors contributed to education-associated disparities in BMI in females.

More than 200 million children aged <5 years fail to reach their full cognitive potential, and children born as twins are particularly at risk. In this article, we review studies that examined differences in the neurodevelopmental outcomes of twins compared to singletons. We searched the Medline database for articles on twins, singletons, neuro, and cognitive development. We also inspected bibliographies of relevant publications to identify related articles from 2011 to 2017. Our search criteria yielded 162 studies, 8 of which met the inclusion criteria. Of the eight studies examined, four were prospective follow-up studies, three were cross-sectional studies, and one was a randomized controlled trial. Five of these studies were carried out in developed countries, and they found no statistically significant difference in neurodevelopmental outcomes among twins and singletons. However, two of the three studies carried out in developing countries found a difference with singletons having significantly higher academic ratings than twins. Studies in which neurodevelopmental outcomes were measured early in life (1–5 years) showed no significant twin–singleton differences, while those in which it was measured later in life showed mixed twin–singleton differences. Overall, these studies may have been underpowered and may not have been optimally designed and implemented. There is need for studies with adequate sample sizes, good design, and optimal measurement of all relevant covariates in order to resolve the conflicting reports in the literature.

Twin researchers face the challenge of accurately determining the zygosity of twins for research. As part of the annual questionnaire between 1999 and 2006, 8,307 twins from the TwinsUK registry were asked to complete five questions (independently from their co-twin) to ascertain their self-perceived zygosity during childhood on up to five separate occasions. This questionnaire is known as the ‘peas in the pod’ questionnaire (PPQ), but there is little evidence of its validation. Answers were scored and classified as monozygotic (MZ), dizygotic (DZ), or unknown zygosity (UZ) and were compared with 4,484 twins with genotyping data who had not been selected for zygosity. Of these, 3,859 individuals (46.5% of those who had a zygosity from PPQ) had zygosity classified by both the PPQ and genotyping. Of the 708 individual twins whose answers meant that they were consistently classed as MZ in the PPQ, 683 (96.5%) were MZ within the genotype data. Of the 945 individual twins consistently classed as DZ within questionnaire, 936 (99.0%) were DZ in the genotype data. Where both twins scored MZ consistently across multiple questionnaires, 99.6% were MZ on genotyping, 99.7% were DZ on genotyping if both twins consistently scored DZ. However, for the initial questionnaire, 88.6% of those scoring as MZ were genotypically MZ and 98.7% DZ. For twin pairs where both scored UZ, 94.7% were DZ. Using the PPQ on a single occasion provided a definitive classification of whether the twin was MZ or DZ with an overall accuracy of 86.9%, increasing to 97.9% when there was a consistent classification of zygosity across multiple questionnaires. This study has shown that the PPQ questionnaire is an excellent proxy indicator of zygosity in the absence of genotyping information.

This article begins with the story of a 51-year-old Los Angeles, California man, Justin Goldberg, whose daughter caught a glimpse of his striking look-alike at a popular market. Many people have so-called doppelgängers, but this occurrence is especially intriguing — the individual in question, born in New York City in the mid-1960s to an unwed mother, was an adoptee placed by the Louise Wise Adoption Agency. This agency, under the guidance of a prominent psychiatrist, decided to place twins in separate homes. Some of these twin children were part of a controversial child development study that was hidden from them and their parents. Next, recent and current twin research on heart transplantation, distinguishing monozygotic co-twins, twin conceptions via oocyte donation and factors affecting craniofacial traits are summarized. The article concludes with highlights on twins in the media, specifically, a triplet delivery in the United Kingdom, self-concept and consciousness in conjoined twins, Colombian twin trainers, skin grafting to save an identical co-twin, lack of physical flaws in Dolly the cloned sheep, possible opposite-sex conjoined twins, and the passing of the remaining twin from the world's longest separated pair.